Key Points
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Hydrogen sulfide (H2S) has emerged as an important gasotransmitter and signalling molecule, akin to nitric oxide (NO) and carbon monoxide (CO).
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H2S is generated from Cys and its derivatives by three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MST).
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H2S has a major role in vasorelaxation and regulation of blood pressure. Mice lacking CSE display substantial cardiovascular dysfunction and hypertension.
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One of the mechanisms by which H2S mediates its effects is via protein sulfhydration, which is analogous to nitrosylation by NO. In the process of sulfhydration, the thiol group of a reactive Cys is modified to an persulfide (-SSH) group, resulting in increased reactivity of the Cys residue. Sulfhydration is more prevalent than nitrosylation, as 25–50% of murine hepatic proteins were found to be sulfhydrated.
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Sulfhydration orchestrates diverse signalling pathways ranging from vasorelaxation to the stress response. The vasoactivity of H2S stems from its ability to sulfhydrate the Kir6.1 subunit of ATP-dependent potassium (KATP) channels to elicit hyperpolarization of vascular smooth muscle cells.
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H2S regulates the endoplasmic reticulum (ER) stress response by sulfhydrating and inhibiting protein Tyr phosphatase 1B (PTP1B), a key player in the ER stress response pathway. H2S also mediates the anti-apoptotic activity of nuclear factor-κB (NF-κB) by sulfhydrating the p65 subunit, thereby augmenting the transcription of pro-survival genes.
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Sulfhydration is a reversible event, a feature that is necessary for the dynamic regulation of signalling pathways.
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Sulhydration and nitrosylation may interface to modulate cellular responses. In the case of stress signalling by NF-κB, sulfhydration of Cys38 precedes its nitrosylation, providing a mechanistic basis for differentiating cell survival from cell death.
Abstract
Hydrogen sulfide (H2S) has recently emerged as a mammalian gaseous messenger molecule, akin to nitric oxide and carbon monoxide. H2S is predominantly formed from Cys or its derivatives by the enzymes cystathionine β-synthase and cystathionine γ-lyase. One of the mechanisms by which H2S signals is by sulfhydration of reactive Cys residues in target proteins. Although analogous to protein nitrosylation, sulfhydration is substantially more prevalent and usually increases the catalytic activity of targeted proteins. Physiological actions of sulfhydration include the regulation of inflammation and endoplasmic reticulum stress signalling as well as of vascular tension.
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This work has been supported by United States Public Health Service Grants (MH018501) to S.H.S.
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Glossary
- Gasotransmitter
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Endogenous gaseous molecule that can act as a messenger in signalling pathways.
- Homocysteinaemia
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A disorder that is characterized by increased homocysteine levels in the blood.
- Astrocytes
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Star-shaped glial cells of the central nervous system that form a structural and functional interface between non-nervous tissues and neurons.
- Sulfane sulfur
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The uncharged form of sulfur (SO), which is attached to proteins through a covalent bond between the SO atom and other sulfur atoms.
- Amperometry
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An electroanalytical technique that measures the current flow through an electrochemical cell. A constant fixed potential is applied to an electrochemical device (such as a sensor or electrode), and the current response, which reflects oxidation or reduction of analytes of interest, is monitored.
- Biotin switch assay
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An assay that detects nitrosylation of Cys residues by replacing the NO moiety with a detectable biotin derivative.
- Acid dissociation constant
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(pKa). A quantitative measure of the tendency of an acid to dissociate in solution. It is calculated as pKa = −log10Ka, in which Ka = [A−][H+]/[HA] and [A−], [H+] and [HA] are the concentration of the dissociated acid, protons and the undissociated (protonated) acid, respectively.
- Thioredoxin system
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Maintains the reducing environment in cells by facilitating electron transfer from NADPH through thioredoxin reductase to thioredoxin, which reduces its target proteins using highly conserved thiol groups.
- Glyceraldehyde-3-phosphate dehydrogenase
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(GAPDH). A glycolytic enzyme that catalyses the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglyceric acid.
- Endothelium-derived relaxing factors
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(EDRFs). Factors derived from endothelial cells of blood vessels that can elicit vasorelaxation. Examples of EDRFs are NO, CO and H2S.
- Cholinergic stimuli
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Refers to molecules that are capable of activating acetylcholine receptors.
- Muscarinic receptors
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Acetylcholine G protein-coupled receptors that are activated by the prototypical agonist, muscarine, a compound isolated from the mushroom Amanita muscaria.
- Calmodulin
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A calcium protein that is found in all eukaryotes. Calmodulin has a high degree of structural conservation, can bind to target enzymes and modulate their activity as a function of cytosolic calcium concentration.
- ATP-dependent potassium channels
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(KATP channels). Potassium channels that are regulated by ATP. Binding of ATP keeps the channel in a closed conformation, preventing the entry of K+ ions.
- Endothelium-derived hyperpolarizing factors
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(EDHFs). Substances derived from the endothelium that act via ion channels to increase the electronegativity of the membrane.
- Resistance blood vessels
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Blood vessels that exhibit increased resistance to blood flow. Vascular resistance is directly proportional to the extent of vasoconstriction, which is one of the primary determinants of blood pressure.
- Normoxic conditions
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Ambient O2 concentrations (∼21%) or, in reference to tissue, O2 concentrations in normal physiological condition (∼2–3%).
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Paul, B., Snyder, S. H2S signalling through protein sulfhydration and beyond. Nat Rev Mol Cell Biol 13, 499–507 (2012). https://doi.org/10.1038/nrm3391
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DOI: https://doi.org/10.1038/nrm3391
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